Ultrasound applied to the skin has two main effects. First, cavitation results from the rapidly oscillating pressure field, causing bubble formation and collapse, which mechanically creates channels through the stratum corneum. The second effect is the direct heating of the material through which the sound waves are travelling, due to attenuation of the acoustic energy through reflection, absorption and dispersion. In skin, this occurs up to four times more than other tissues due to its heterogeneity. Heating is known to disrupt the lipid bilayer system in the stratum corneum also contributing to the enhanced permeability of the epidermis.
It is known that ultrasound can be used to deliver molecules to within the skin. When ultrasound is used in this context it is termed “sonophoresis”. The permeability of the skin is increased by disruption of the intercellular lipids through heating and/or mechanical stress, and through the increase in porosity. Continuous mode ultrasound at an intensity of 1 W/cm2 raises the temperature of tissue at a depth of 3 cm to around 40° C. in 10 minutes. For smaller molecules, such as mannitol, enhancement of permeation through the skin occurs when ultrasound is applied as a pre-treatment or simultaneously with application of the molecule; whereas for large molecules such as insulin, enhancement of permeation has only been recorded during application of ultrasound.
Cosmetic treatments that aim to improve skin quality are also hindered by the barrier function of the epidermis and in particular the outer stratum corneum. The epidermis provides a significant mechanical and chemical barrier to solute transfer due to the cornified cell/lipid bilayer. Also, there is significant enzymatic activity in the epidermis and dermis, which provides a biochemical defense to neutralise applied xenobiotics and which is comparable to that of the liver in terms of activity per unit volume. Additionally, the molecular weight of active substances is known to be important in determining their propensity to diffuse across the skin. Diffusion of substances of molecular weight around 500 Da and above is known to be inefficient. Methods and apparatus involving ultrasound have been described for use in cosmetic of the skin and in medical treatments.
To be effective, treatment for cosmetic skin conditions, such as skin ageing and sun damage, must deliver actives to at least the depth of the upper (papillary) dermis and therefore must employ a mechanism to overcome this effective physical and biochemical barrier, even when it has deteriorated with age.
Increasingly, low frequency ultrasound (e.g. <100 kHz) is being recogniseda as more effective in enhancing transdermal drug/solute delivery (sonophoresis) due to its greater mechanical/non-thermal mode of cavitation and acoustic streaming. These mechanisms create temporary channels and force solutes through the otherwise impermeable stratum corneum of the skin. Higher frequencies do also have some benefits in solute delivery but this is largely attributed to more thermal effects whereby intercellular lipids are disruptedb. a Mitragotri et al, 1996, Transdermal drug delivery using low frequency sonophoresis, Pharm. Res., 13, 411-420.b Lavon & Kost, 2004, Ultrasound and transdermal delivery, Drug Discovery Today, 9(15), August.
Higher frequencies, typically 1-3 MHz, have traditionally been employed for therapeutic effect such as in physiotherapyc. This is due to its ability to improve vascularity, protein expression and cytokine responses in cells. Most physiotherapy devices adopt frequencies in the high frequency range and can deliver either 1 MHz or 3 MHz or both (from separate transducer components). Frequencies above 3 MHz are rarely employed as only a small proportion of the acoustic energy will be delivered to target areas where physiotherapy would be needed such as muscles and ligaments. The ½ thickness values (depths at which respective frequencies decay to 50% of original intensity) for 1, 3 and 5 MHz are typically 9 cm, 2.5 cm and 1.25 cm through homogenous tissue respectivelyd indicating that only superficial soft tissue targets would benefit from frequencies of 3 MHz or above. c Kitchen S S, Partridge C. J. A review of therapeutic ultrasound. Physiotherapy. 1990; 76:593-600d Ultrasonic Biophysics, Gail ter Haar, Physical Principles of Medical Ultrasonics. Edited by C. R. Hill, J. C. Bamber and G. R. ter Haar.©2003 John Wiley & Sons, Ltd: ISBN 0 471 97002 6
Strict separation of application categories between low frequency (solute delivery) and high frequency (therapy) is not entirely appropriate as both frequency ranges have efficacy in both delivery and therapye. However, it is recognised that the two frequency ranges interact with hard and soft tissue in predominantly different ways: i.e. low frequency—via mechanical/non-thermal effects; and high frequency—via thermal effects. e Reher P.; Doan N.; Bradnock B.; Meghji S.; Harris M., Effect of ultrasound on the production of IL-8, basic FGF and VEGF, Cytokine, Volume 11, Number 6, June 1999, pp. 416-423(8)
For the treatment of dermal conditions, it is desirable to be able to exert both a therapeutic effect in the skin (e.g. increased vascularity and protein expression) and to enhance delivery of targeted actives into and through the skin. It is therefore logical that a dermatological ultrasound treatment would employ both frequency ranges to yield maximum efficacy, especially when used with a coupling gel that contains actives targeted at that specific condition.
Traditionally, therapeutic ultrasound devices that are capable of emitting more than one frequency have been limited to high frequencies, e.g. 1 and 3 MHz. The Chattanooga Intellect Legend Dual Frequency Ultrasound machine is an example. One device has been developed and marketed to emit both a low frequency and a high frequency; that being the SRA Developments ‘Duoson’ unit, which operates at 45 kHz and 1 MHz.
The Duoson device has spatially adjacent transducer elements comprising a centrally located circular high frequency transducer (1 MHz) and a low frequency (45 kHz) annular ring transducer encircling the central transducer. As with other therapeutic ultrasound devices, this dual frequency ultrasound device has a hand-held head/probe which requires constant manual manipulation/movement to treat areas of the body.
Constant movement of hand-held devices is important to avoid over and under exposure. Over-exposure can lead to over-heating/thermal damage and also standing waves being created with the potential to cause lysis of cells. Conversely, under-exposure will reduce the amount of ultrasonic energy received by a particular area of the body and therefore cause reduced therapeutic benefit.
Relying on manual movement of the device is unreliable and cannot guarantee even coverage and therefore exposure. Some areas will not receive the same level of treatment as others and are highly dependent on the abilities of the practitioner to keep the device moving at a constant steady speed, potentially over a 20-30 minute period. Such manipulation can lead to arm/wrist/hand fatigue and thus uneven treatment of the patient.
This would be an even greater problem if a device required emission of two frequency regimes and the two transducers were configured adjacently. In such a case, areas of skin and other underlying areas of the body might receive disproportionately more energy at one frequency than at another, if the device was not moved evenly over the area to be treated.
As shown in FIG. 1, WO2006/040597 generally discloses a treatment patch 100 that contains a plurality of transducer elements 110 arranged as an array and held in proximity to each other by compliant material 112, such as a silicone rubber layer. Each element 110 is individually connected to a power source via spring connectors 117 attached to juxta-positioned contacts 118 on a flexibly mounted plate 120. The transducer array may then be connected to an ultrasound generator via connectors 122. The transducer elements 110 can thus be driven by respective low and high frequency voltages in order to emit low and high frequency ultrasound.
Such an arrangement overcomes the aforementioned problems with hand-held devices, because if such a thin, flexible array is placed over a site to be treated then the area beneath the array will receive both high and low frequency ultrasound. If the activation of the transducers is also swept across the array, i.e. sequentially activating/deactivating rows, columns or other sub-groups of transducer elements, then the device will deliver a uniform treatment to the chosen area, overcoming problems with hot and cold spots (over and under exposure to the desired ultrasound). This will obviate operator error due to inconsistent movement of an otherwise hand-held device.
Moreover, each transducer element 110 may comprise two components: a high frequency transducer element, e.g. a piezo ceramic disc element 114 and a low frequency transducer element, e.g. a PVDF element 116. The upper surface of the piezo ceramic element 114 and the lower surface of the PVDF element 116 may be connected together electrically. FIG. 1c shows a particular form of the transducer element 110 in which the piezo ceramic disc 114 is conductively attached to a metal element 124 which in turn is conductively attached to the PVDF element 116 via a metal ring 126 and insulating spacer ring 128. A common voltage connection is achieved via a conductive ring 130. Alternate drive frequencies of 50 kHz and 1 MHz are generated either by individual circuits or via DDS chip, and the combined transducer 110 is alternatively energised in bursts of 50 kHz and 1 MHz sine wave pulses.
Such uniaxially mounted elements 114,116 allow multiple frequency emission along a common axis. This would obviously increase the number of components that need to be assembled, increase the weight of what is intended to be a lightweight flexible patch and also increase the thickness. Extra thickness, wiring and mounting of several transducers in this way would also adversely affect the radius of curvature that the patch could bend to, so minimising the different human or animal body sites to which the patch could conform.